Chemical formula: C₁₆H₂₁N₃O₂ Molecular mass: 287.357 g/mol PubChem compound: 60857
Zolmitriptan has been demonstrated to be a selective agonist for 5HT1B/1D receptors mediating vascular contraction. Zolmitriptan has high affinity for human recombinant 5HTIB and 5HTID receptors, and modest affinity for 5HTIA receptors. Zolmitriptan has no significant affinity or pharmacological activity at other 5HT receptor subtypes (5HT2, 5HT3, 5HT4) or adrenergic, histaminic, muscarinic or dopaminergic receptors.
The 5HT1B/1D receptor is predominantly located presynaptically at both the peripheral and central synapses of the trigeminal nerve and preclinical studies have shown that zolmitriptan is able to act at both these sites.
In animal models, the administration of zolmitriptan causes vasoconstriction in the carotid arterial circulation. In addition, experimental studies in animals suggest that zolmitriptan inhibits central and peripheral trigeminal nerve activity with inhibition of neuropeptide release (calcitonin gene related peptide (CGRP), vasoactive intestinal peptide (VIP) and Substance P).
Following oral administration of zolmitriptan conventional tablets, zolmitriptan is rapidly and well absorbed (at least 64%) after oral administration to man. The mean absolute bioavailability of the parent compound is approximately 40%. There is an active metabolite (the N-desmethyl metabolite) which is also a 5HT1B/1D receptor agonist and is 2 to 6 times as potent, in animal models, as zolmitriptan.
In healthy subjects, when given as a single dose, zolmitriptan and its active metabolite, the N-desmethyl metabolite , display dose-proportional AUC and Cmax over the dose range 2.5 to 50mg. Absorption of zolmitriptan is rapid. In healthy volunteers, 75% of Cmax is achived within 1 hour, and after this the concentration of zolmitriptan in plasma is maintained at approximately this level until 4-5 hours after dosing.
Zolmitriptan absorption is unaffected by the presence of food. There was no evidence of accumulation on multiple dosing of zolmitriptan.
Plasma concentration of zolmitriptan and its metabolites are lower in the first 4 hours after drug administration during a migraine compared with a migraine-free period, suggesting delayed absorption consistent with the reduced rate of gastric emptying observed during a migraine attack.
Zolmitriptan orodispersible tablet was demonstrated to be bioequivalent with the conventional tablet in terms of AUC and Cmax for zolmitriptan and its active metabolite 183C91. Clinical pharmacology data show that the tmax for zolmitriptan can be later for the orally dispersible tablet (range 0.6 to 5h, median 3h) compared to the conventional tablet (range 0.5 to 3h, median 1.5h). The tmax for the active metabolite was similar for both formulations (median 3h).
Zolmitriptan is eliminated largely by hepatic biotransformation followed by urinary excretion of the metabolites. There are three major metabolites: the indole acetic acid, (the major metabolite in plasma and urine), the N-oxide and N-desmethyl analogues. The N-desmethylated metabolite is active whilst the others are not. Plasma concentrations of the N-desmethylated metabolite are approximately half those of the parent drug, hence it would therefore be expected to contribute to the therapeutic action of zolmitriptan. Over 60% of a single oral dose is excreted in the urine (mainly as the indole acetic acid metabolite) and about 30% in faeces mainly as unchanged parent compound.
Following intravenous administration, the mean total plasma clearance is approximately 10 ml/min/kg, of which one quarter is renal clearance. Renal clearance is greater than glomerular filtration rate suggesting renal tubular secretion. The volume of distribution following intravenous administration is 2.4 L/kg. Plasma protein binding of zolmitriptan and the N-desmethyl metabolite is low (approximately 25%). The mean elimination half-life of zolmitriptan is 2.5 to 3 hours. The half-lives of its metabolites are similar, suggesting their elimination is formation-rate limited.
Renal clearance of zolmitriptan and all its metabolites is reduced (7-8 fold) in patients with moderate to severe renal impairment compared to healthy subjects, although the AUC of the parent compound and the active metabolite were only slightly higher (16 and 35% respectively) with a 1 hour increase in half-life to 3 to 3.5 hours. These parameters are within the ranges seen in healthy volunteers.
The metabolism of zolmitriptan is reduced in hepatic impairment in proportion to the extent of the impairment. Zolmitriptan AUC and Cmax were increased by 226% and 50%, respectively and the half life was prolonged to 12 h in subjects with severe liver disease compared to healthy subjects. Exposure to the metabolites, including the active metabolite was reduced.
The pharmacokinetics of zolmitriptan in healthy elderly subjects were similar to those in healthy young volunteers.
Zolmitriptan, following intranasal administration, is rapidly absorbed with detectable levels in the plasma within 5 minutes of dosing. A proportion of the dose seems to be directly absorbed in the naso-pharynx. On average 40% of Cmax of the parent compound, zolmitriptan, is achieved within 15 minutes. The appearance in plasma of the active metabolite, 183C91, which is partly formed through first-pass metabolism, is delayed by 15 to 60 minutes post-dose. Cmax of the parent compound, zolmitriptan is achieved after 3 hours. Plasma concentrations are sustained for up to 4 to 6 hours.
Elimination of zolmitriptan and the active metabolite 183C91 after oral and intranasal delivery appear similar; the mean elimination half-life (t½) for both zolmitriptan and 183C91 are approximately 3 hours. The bioavailability of intranasal relative to oral administration is 102%. In healthy volunteers after single and multiple intranasal doses, zolmitriptan and its active metabolite 183C91 display dose proportional AUC and Cmax over the range 1 to 5 mg. There is no evidence of accumulation of zolmitriptan after multiple intranasal dosing.
The plasma concentrations and elimination pharmacokinetics of zolmitriptan and the three major metabolites for the nasal spray and conventional tablet formulations are similar.
The plasma half-life (T½) of zolmitriptan was 4.7 hours in healthy volunteers, 7.3 hours in patients with moderate liver disease and 12 hours in those with severe liver disease. The corresponding T½ values for the 183C91 metabolite were 5.7 hours, 7.5 hours and 7.8 hours respectively. No studies have been undertaken to characterise the pharmacokinetics of intranasally administered zolmitriptan in patients with hepatic impairment.
In a small group of healthy individuals there was no pharmacokinetic interaction with ergotamine. Concomitant administration of Zomig with ergotamine/caffeine was well tolerated and did not result in any increase in adverse events or blood pressure changes as compared with Zomig alone (see Section 4.5). These findings originate from studies with zolmitriptan tablets.
Selegiline, an MAO-B inhibitor, and fluoxetine (a selective serotonin reuptake inhibitor; SSRI) had no effect on the pharmacokinetic parameters of zolmitriptan. These findings originate from studies with zolmitriptan tablets.
Following the administration of rifampicin, no clinically relevant differences in the pharmacokinetics of zolmitriptan or its active metabolite were observed. The findings originate from studies with zolmitriptan tablets.
The pharmacokinetics of zolmitriptan in healthy elderly subjects were similar to those in healthy young volunteers. These findings originate from studies with zolmitriptan tablets.
The absorption of zolmitriptan nasal spray in healthy volunteers was found unaltered when administered concomitantly with the sympathomimetic nasal decongestant, xylometazoline.
Preclinical effects in single and repeat dose toxicity studies were observed only at exposures well in excess of the maximum human exposure.
The findings from in vitro and in vivo genetic toxicity studies show that genotoxic effects of zolmitriptan are not to be expected under the conditions of clinical use.
No tumours relevant to the clinical use were found in mouse and rat carcinogenicity studies.
An oral teratology study of zolmitriptan has been conducted. At the maximum tolerated doses of zolmitriptan, 1200 mg/kg/day (AUC 605 μg/ml.h: approx. 3700 x AUC of the human maximum recommended daily intake of 15 mg) and 30 mg/kg/day (AUC 4.9 μg/ml.h: approx. 30 x AUC of the human maximum recommended daily intake of 15 mg) in rats and rabbits, respectively, no signs of teratogenicity were apparent.
As with other 5HT1B/1D receptor agonists, zolmitriptan binds to melanin.
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